Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease

Abstract

The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause several forms of CMT neuropathy, but the pathogenic mechanisms involved remain unclear. GDAP1 is an outer mitochondrial membrane protein highly expressed in neurons. It has been proposed to play a role in different aspects of mitochondrial physiology, including mitochondrial dynamics, oxidative stress processes, and mitochondrial transport along the axons. Disruption of the mitochondrial network in a neuroblastoma model of GDAP1-related CMT has been shown to decrease Ca²⁺ entry through the store-operated calcium entry (SOCE), which caused a failure in stimulation of mitochondrial respiration. In this review, we summarize the different functions proposed for GDAP1 and focus on the consequences for Ca²⁺ homeostasis and mitochondrial energy production linked to CMT disease caused by different GDAP1 mutations.

Keywords: GDAP1; calcium regulated cell respiration; mitochondrial location; recessive mutations; store operated calcium entry.

Figure 1

Effects of ganglioside-induced differentiation-associated protein 1 (GDAP1) on mitochondrial bioenergetic functions. (A) Interaction between GDAP1 and the trafficking proteins allows mitochondria to be located close to the plasma membrane after store-operated calcium entry (SOCE) activation, preventing its Ca²⁺-dependent inactivation. Ca²⁺ uptake by mitochondria facilitates SOCE but also regulates ATP production by oxidative phosphorylation. Ca²⁺-dependent regulation of OXPHOS involves two main mechanisms (dotted red arrows); (i) Ca²⁺ entry through the mitochondrial Ca²⁺ uniporter complex (MCUc) and the activation of dehydrogenases of the tricarboxylic acid cycle (TCA), and (ii) activation of the neuronal Ca²⁺-dependent mitochondrial transporters of aspartate/glutamate (Aralar) or ATP-Mg/Pi (SCaMC-3). Aralar activation increases Malate/Aspartate shuttle (MAS) activity, transferring reducing equivalents from NADH to mitochondria and thereby increasing pyruvate (Pyr) supply to mitochondria to enhance mitochondrial respiration. SCaMC-3 activation increases mitochondrial adenine nucleotide pool (solid and dotted black arrows); (B) Mitochondrial movement might be affected by recessive mutations located in the α-loop of GDAP1 causing the loss of interaction with trafficking proteins RAB6B and caytaxin which might affect the proper mitochondrial localization at the subplasmalemmal microdomains and disturb SOCE activity (red T bar). Subsequently, this will also impair mitochondrial bioenergetic functions by either decreasing Ca²⁺ uptake by MCUc and activation of matrix dehydrogenases, and/or by decreasing the activation of Ca²⁺-dependent mitochondrial transporters.